Compounds for preparing 6-phenyl-2,3-dihydroimidazo[2,1-b]-thiazoles and corresponding thiazines

ABSTRACT

6-Aryl-2,3-dihydroimidazo[2,1-b]thiazoles and corresponding thiazines act as nucleophiles, either directly or in the form of Grignard reagents, with N-acylpyridinium salts to produce new 6-aryl-5-(N-acyl-1,4-dihydro-4-pyridyl)-2,3-dihydroimidazo-[2,1-b]thiazoles and corresponding thiazines. These are oxidized to give the corresponding pyridyl-substituted imidazo[2,1-b]thiazoles and thiazines, which are active as inhibitors of the 5-lipoxygenase pathway of arachidonic acid metabolism.

This is a division of application Ser. No. 06/856,246 filed Apr. 28,1986 now U.S. Pat. No. 4,803,279 issued Feb. 7, 1989, which is acontinuation-in-part of application Ser. No. 06/737,137 filed May 23,1985, now abandoned, which is a continuation-in-part of Ser. No.06/808,595 filed Dec. 12, 1985, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to new intermediates and processes for preparing5-(4-pyridyl)-6-phenyl-2,3-dihydroimidazo[2,1-b]thiazoles andcorresponding thiazines which have activity as inhibitors of the5-lipoxygenase pathway of arachidonic acid metabolism.

Certain anti-arthritic 5,6-diaryl-2,3-dihydroimidazo[2,1-b]thiazoles aredescribed in U.S. Pat. No. 4,175,127. The method disclosed therein forpreparing them includes a ring closure of the corresponding4,5-diaryl-2-mercaptoimidazole. If the substituents at the 4,5-positionsof the 2-mercaptomidazole are different, the position isomers at the5,6-positions of the end product 2,3-dihydroimidazo-[2,1-b]thiazoles areproduced in about equal quantities. In most cases, and certainly withthe preparation of the preferred5-(4-pyridyl)-6-(4-fluorphenyl)-2,3-dihydroimidazo-[2,1-b]thiazole, theposition isomers are separated with difficulty, and even the mostefficient separation techniques, preferably using column separation,provide less than 50% yield of the preferred isomer. In practical fact,however, overall yields are much lower. The present invention greatlyreduces the cost of chemical for the preparation of the biologicallyactive 5-pyridyl-6-aryl compounds.

Direct addition of various organic moieties to a pyridine ring throughthe use of Grignard reagents or other organometallic salts is known. Forexample, it is shown by K. Akiba et al., Tetrahedron Letters, 23, 429(1982), that 4-alkylpyridines can be prepared with high regioselectivityby reacting a 1-acylpyridinium salt with an alkylcopper-borontrifluoride complex. The synthesis of 1-acyl-4-alkyl(oraryl)-1,4-dihydropyridines by reacting the appropriate alkyl or arylGrignard reagent with 1-acylpyridinium salt, in the presence of cuprousiodide, is shown in Comins, Tetrahedron Letters, 24, 2807 (1983) andComins et al, J. Org. Chem., 47, 4315 (1982).

Direct addition of imidazo-thiazole or -thiazine moieties to pyridine,however, has not been previously shown by these methods. The fused-ringGrignard reagents necessary for direct addition to the pyridinium salthave heretofore been unavailable. Nor has it been suggested previouslythat a 6-phenyl-imidazo[2,1-b]thiazole (or the corresponding thiazine),by acting as a nucleophile at its 5-position, could bypass the metallicintermediate entirely and add directly to pyridine, particularly withselectivity for the 4-position. The present invention, however, providesmethods by which this direct regiospecific addition of the fused-ringmoiety can be effected, either by direct nucleophilic attack or by useof novel Grignard intermediates. Accordingly, the present inventionavoids the yield loss resulting from the prior art's production of5,6-position isomers during ring-closure of the correspondingmercaptoimidazole.

SUMMARY OF THE INVENTION

The present invention relates to new compounds having the basicstructure of a5-(N-acyl-l,4-dihydro-4-pyridyl)-6-phenyl-2,3-dihydroimidazo[2,1-b]-thiazoleor the corresponding thiazine (compounds of Formula I) and to twoprocesses for preparing such compounds: ##STR1## in which: A is --CH₂ --or --CH₂ CH₂ --;

B and D are independently H, methyl, ethyl, or dimethyl;

R is

(a) phenyl;

(b) monosubstituted phenyl wherein the substituent is halogen, C₁ -C₃alkoxy, C₁ -C₃ alkylthio, C₁ -C₄ alkyl, CF₃, 2,2,2-trihaloethoxy,prop-2-ene-1-oxy, C₁ -C₃ dialkylamino, N-(C₁ -C₃ alkyl)-(C₁ -C₃alkanamido), or N-azacycloalkyl of 5 or 6 carbon atoms;

(c) disubstituted phenyl wherein the substituents are independently C₁-C₄ alkyl or C₁ -C₃ alkoxy, or the substituents together form amethylene-dioxy group; or

(d) 3,4,5-trimethoxyphenyl;

R² is H or ##STR2## and R¹ is C₁ -C₈ alkyl, C₁ -C₈ alkoxy, phenyl,phenoxy, benzyl, or benzyloxy.

The processes of the present invention by which the Formula I compoundsare prepared involve nucleophilic addition to a 1-acylpyridinium salt.In one of these processes, a 6-phenyl-imidazo[2,1-b]thiazole or thecorresponding thiazine is reacted directly with the pyridinium salt. Inthe other process, the imidazo-thiazole (or thiazine) is converted toits corresponding Grignard reagent prior to reaction with the pyridiniumsalt. Another aspect of the present invention provides the novelGrignard reagents themselves and a method by which they are prepared. Inyet another aspect of the present invention, a method of oxidizing thedihydropyridine compounds of Formula I to their pyridyl derivatives,which have activity as inhibitors of the 5-lipoxygenase pathway ofarachidonic acid metabolism activity, is provided.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to new intermediates and processes for preparingbiologically active final products which are5-(4-pyridyl)-6-phenyl-2,3-dexydroimidazo[2,1-b]thiazoles and thiazides(hereinafter referred to as "biologically active final products"). Allof the biologically active final products have activity as in vivoinhibitors of the 5-lipoxygenase pathway of arachidonic acid metabolismin animals, such as man and other mammals, and some are also useful aintermediates in the preparation of compounds which have activity as invivo inhibitors of the 5-lipoxygenase pathway in animals such as man andother mammals (as disclosed in Bender et al., U.S. Ser. No. 808,595,filed Dec. 12, 1985 and Bender et al., U.S. Ser. No. 856,875, titled"Inhibitors of the 5-Lipoxygenase Pathway", filed simultaneously withthe subject application, the disclosure of both of which is herebyincorporated by reference), and some of the biologically active finalproducts also have activity as inhibitors of the cyclooxygenase pathwayof arachidonic acid metabolism (as disclosed by their activity in theadjuvant arthritic rat model in Bender et al., U.S. Pat. No. 4,175,127,the disclosure of which is hereby incorporated by reference).

Compounds of Formula I are prepared according to one aspect of thisinvention by reaction (A): ##STR3## in which: A, B, D, and R are asdescribed above;

R¹ is the non-reactive residue of a reactive acyl ester, especially anacyl halide, such as C₁ -C₈ -alkyl, C₁ -C₈ -alkoxy, phenyl, phenoxy,benzyl or benzyloxy; and

X is an anion commonly associated with acyl cations or equivalent to thesame. Particularly useful is a reactive halogen such as iodo, chloro orbromo. Other anions are acetate, propionate, triflate(trifluoromethylsulfonate), tosylate (p-toluenesulfonate), mesylate(methylsulfonate) or boron tetrafluoride.

The starting materials for this process for Formula II compounds inwhich A=CH₂ (thiazole) are described in S. Kano, Yakugaku Zasshi, 9251-58 (1972), which, in general, describes that6-phenyl-2,3-dihydroimidazo[2,1-b]thiazoles can be prepared by heatingthe corresponding 2-amino-4,5-dihydrothiazole with the appropriatelysubstituted phenacyl bromide in an organic solvent, followed bytreatment with an alkali such as NaOH to recover the compound from itshydrobromide.

Starting materials for Formula II compounds in which A is CH₂ -CH₂(thiazine) can be prepared in an analogous manner to the Kano process,described above, from the corresponding2-amino-5,6-dihydro-4H-1,3-thiazine. More particularly, 7-(4-substitutedphenyl)-2,3-dihydro-4H-imidazo [2,1-b]-(1,3)thiazines can be prepared byreacting the corresponding 2-amino-5,6-dihydro-4H-1,3-thiazine with4-substituted bromoacetophenones in a non-polar solvent such as benzeneor chloroform, to form an intermediate which is then refluxed in water.See, Schoeberl, et al., Justus Liebigs Ann. Chem., 742, 85-97 (1970). Ithas also been found that a polar solvent can be used as well, and thatthe intermediate may or may not be isolated prior to the refluxing step.The amino-thiazine starting material can be prepared by treating3-bromopropylamine with t-butyl isothiocyanate, followed by refluxtreatment with HBr or HCl. See, for example, Schubert, et al., Arch.Pharm., 301(10), 750-762 (1968).

The reaction (A) is carried out by reacting the6-arylimidazo[2,1-b]thiazole or thiazine analog of Formula II with anexcess of both the pyridine and the reactive acyl ester reactant in anorganic solvent in which the reactants ar soluble and with which thereactants, especially the acyl ester, are inert. One skilled in the artwill recognize that the pyridine and acyl ester react to form theacylpyridinium reagent of Formula III in situ. Optionally, theacylpyridinium reagent can be prepared separately in a solvent and thenadded to the solution of Formula II compound. Suitable solvents includemethylene chloride, ethylene chloride, chloroform, carbon tetrachloride,tetrahydrofuran, ethyl ether, dioxane, toluene, or excess pyridine.

In the conduct of reaction A, the reaction mixture is cooled during themixing of the reactants, preferably to a temperature between 5°-20° C.,by use of an ice/water bath. The mixture is then allowed to standbriefly at ambient temperature, followed by refluxing until reaction iscomplete. The reaction mixture is continually assayed using highperformance liquid chromatography (HPLC) or thin layer chromatography(TLC) on aliquots to ascertain if unreacted Formula II compound ispresent. If so, additional acyl pyridinium salt is introduced. Otherconditions of the reaction are standard to the art. Following thereaction, the resultant Formula I compounds can be recovered from thereaction mixture and isolated by standard techniques, or the reactionmixture (with no isolation of the Formula I compounds) can be used asthe medium for the oxidation step described below as reaction (D).

Compounds of Formula I wherein R² is ##STR4## can be prepared accordingto another aspect of this invention by reaction (B): ##STR5## in whichX' is Cl, Br, or I (preferably Br); and R, R¹, X, A, B, and D are asdescribed earlier, provided, however, that R is other than N-(C₁ -C₃alkyl) however (C₁ -C₃ alkanamido) phenyl.

Reaction (B) is conducted by contacting the Grignard reagent (FormulaIV) with an excess of both the pyridine and the selected reactive acylester in a solvent appropriate for Grignard-reagent use. Examples ofsuch solvents include, but are not limited to, dry ethers such as ethylether, or preferably, tetrahydrofuran. The Grignard reagent can becombined with the pyridine and the acyl ester in sequence, or as inreaction (A) above, the pyridinium salt can be prepared separately andthen added to the solution of Grignard reagent. Preferably, the reactionis conducted by the addition of 2-6 moles of pyridine to each mole ofthe Grignard reagent, followed by addition of at least an equimolaramount of the acyl compound.

In the conduct of reaction (B), the reactants are mixed into thesolvent, with cooling, preferably to a temperature of -10° C. or below.During the mixing period, at least about 5 mole % of cuprous iodide(CuI), based on the molar quantity of pyridine present, is introduced tothe reaction mixture to insure the ultimate addition of the Grignardreagent at the 4-position of the N-acyl-1,4-dihydropyridine compound.

When the reactants have been thoroughly dissolved, the reactioninitiates autogenously and the mixture can be permitted to warm to atemperature of about 20° C., but preferably no higher than about 15° C.Aliquots of the reaction mixture are extracted continuously and assayedusing HPLC or TLC to determine the presence of unreactedimidazo[2,1-b]thiazole or thiazine. The conditions of the reaction areotherwise standard for those pertaining to Grignard synthesis ingeneral. As with the Formula I compounds prepared by reaction (A),recovery and isolation can be effected by standard techniques, or thereaction mixture (without isolation of the Formula I compounds) can beused as the medium for the oxidation step of reaction (D) below.

The Grignard reagents of Formula IV are novel compounds which embodyanother aspect of this invention. The Formula IV reagents are preparedby reaction (C): ##STR6## in which A, B, D, and R are as earlierdefined; X' is Cl, Br, or I, preferably Br; X" is Cl or Br; and R³ is C₁-C₅ alkyl, preferably butyl and most preferably n-butyl. The reaction(C) is conducted in an ether solvent, preferably tetrahydrofuran, at atemperature below 0° C. More specifically, the halogenated startingcompound of Formula V is reacted with at least an equimolar amount ofthe alkyllithium compound at a temperature of from about -80° C. toabout -30° C. Following the lithium-halogen exchange, from which theorganolithium compound of Formula VI results, the magnesium halideetherate is added to the mixture in excess and reacted with theorganolithium compound of Formula VI, during which the reactiontemperature can be permitted to rise to a temperature up to about 0° C.,although a reaction temperature below about -10° C. is preferred. TheGrignard reagent of Formula IV which is prepared in this manner ispreferably used immediately in reaction (B), as described above. This ismost easily effected by the addition of cuprous iodide and pyridine,followed by addition of the selected acyl ester to the final reactionmixture of reaction (C).

The starting compounds of Formula V which are used in reaction (C) canbe prepared by halogenating the 6-arylimidazo[2,1-b]thiazole or thiazineof Formula II described above. Halogenation is effected by standardtechniques, which in general include treating the Formula II compoundwith Br₂ or Cl₂ in a neutral solvent at an elevated temperature. Forexample, 5-bromo-6-phenyl-2,3-dihydroimidazo[2,1-b]thiazole can beprepared by reacting the unbrominated starting material of Formula IIwith an equimolar amount of Br₂ in methylene chloride at refluxtemperature. See, S. Kano, Yakagaku Zasshi, 92, 51-58 (1972).

Irrespective of which reaction route, (A) or (B), is chosen, thecompounds of Formula I wherein R² is ##STR7## are preferably preparedwith the most economical pyridinium salt reagents. Examples of suchreagents are those in which R¹ is ethoxy, methoxy, methyl, or phenyl.

Overall , the preferred compounds of formula I are as follows: ##STR8##in which R¹ is ethoxy, methoxy, methyl, or phenyl; A, B, and D are asdescribed above; and R is H, C₁ -C₂ alkyl, C₁ -C₂ alkoxy,trifluoromethyl, N-azacycloalkyl of 5 or 6 carbon atoms, or halogen,preferably F, Cl, or Br. Most preferable are compounds of the preferredclass in which B and D are hydrogen, A is --CH₂ --(thiazole), and R is For Cl, particularly in the 4-position.

In another aspect of the invention, the compounds of Formula I aredeacylated and oxidized to form the biologically active final product ofFormula VII, as shown in reaction (D): ##STR9## in which R² is ##STR10##and R, A, B, and D are as defined earlier. Compounds of Formula I inwhich R² is hydrogen are intermediates that are formed in situ duringthe oxidation reaction (D), and as such they are not usually isolatedduring the reaction sequence, although isolation by standard techniquesis possible if desired.

In the conduct of reaction (D), the dihydropyridine of Formula I isreacted with an appropriate oxidizing agent in an inert solvent systemuntil the starting material has been exhausted, as. monitored, forexample, by periodic TLC or HPLC analysis. Normally, the oxidizing agentis relatively mild, so as to avoid oxidizing the nuclear nitrogen orsulfur members to their respective oxide derivatives. Exemplaryoxidation systems are sulfur (S₈) in decalin, tetralin, p-cymene, orxylene as solvent; or chloranil, oxygen gas, manganese oxide, cericchloride, chromium oxide, hydrogen peroxide or ferricyanide in inertsolvents. When the N or S oxide derivatives are the desired endproducts, a stronger oxidizing agent, such as meta-chloroperbenzoicacid, can be used in excess. Preferred reaction conditions, however, arereaction of a dihydropyridine with sulfur in refluxing xylene or withoxygen in the presence of tert.-butanol/potassium tert.-butoxide.

In general, the oxidation reaction proceeds rapidly, normally within onehour, at a temperature range of from ambient (about 23° C.) for oxygenuse, to solution reflux temperature, for sulfur use. The oxidizedproducts of formula VII are isolated and purified using methods standardin the art.

EXAMPLES

The following examples are illustrative, but not limiting of, theoperation of this invention. All temperatures are in °C.

EXAMPLE 1

(A) 6-(4-Fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole (1 mmol, 220mg) was placed in a clean, dry flask along with a Teflon-coated stirbar. Tetrahydrofuran (10 ml, distilled from sodium/benzophenone) wasadded by syringe and stirring was begun. Pyridine (1 ml) was added bysyringe. The reaction flask was cooled in an ice/water bath. Ethylchloroformate (6.3 mmol, 0.60 ml) was added by syringe. The pinkheterogeneous solution was allowed to stir for 15 hours. The reactionwas then heated to 70° for 45 minutes. The reaction was allowed to cool.The solvent was evaporated off in a rotary evaporator. The residue wastreated with 10% potassium carbonate solution (25 ml). The mixture wasextracted with methylene chloride (2×100 ml). The separated methylenechloride phase was dried over anhydrous sodium carbonate, filtered andconcentrated in a rotary evaporator. The residue was dissolved inmethylene chloride (1 ml) and poured into hexane (50 ml). The resultingheterogeneous solution was filtered and concentrated in a rotaryevaporator to give5-(N-ethoxycarbonyl-1,4-dihydro-4-pyridyl)-6-(4-fluoropheny)-2,3-dihydroimidazo[2,1-b]-thiazole,as a thick oil (80 mg, 22%).

(B) 6-(4-Fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole (2 mmol, 440mg) was placed in a flask along with a Teflon-coated stir bar. A mildflow of dry nitrogen was begun and continued throughout the reaction.Pyridine (10 mmol, 790 mg) was added to form a slurry. The reactionvessel was cooled in an ice bath for 5 minutes, then ethyl chloroformate(4 mmol, 0.382 ml) was added over a 1 minute period. The solutionsolidified. The ice bath was removed and replaced by an oil bath. Theoil was heated to 75° over a 45 minute period and then allowed to cool.The product was taken up in methylene chloride (100 ml) and extractedwith 5% potassium carbonate solution (50 ml). The aqueous layer wasback-extracted with methylene chloride (50 ml). The organic layers werecombined, dried over sodium sulfate and filtered. The filtrate wasconcentrated in a rotary evaporator. The resulting oil was purified bysilica gel chromatography (1:1, ether/hexane/2 % methanol) to yield the1,4-dihydro compound (300 mg, 40%) as a white crystalline solid, m.p.139°-141°.

Anal. Calcd. for C₁₉ H₁₈ N₃ O₂ SF; C, 61.44; H, 4.88; N, 11.31. Found:C, 61.32; H, 4.77; N, 11.38.

(C) 6-(4-Fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole (1 mol, 220 g)was placed in a 5L flask along with a large Teflon-coated stir bar. Alight flow of dry nitrogen was passed through the system. Methylenechloride (400 ml) was added and stirring was begun. Pyridine (11.2 mol,900 ml) was added all at once. The reaction flask was then placed in alarge ice bath and stirred for 10 minutes. Ethyl chloroformate (4.35mol, 354 ml) was charged into an addition funnel and slow dropwiseaddition was begun. After 1 hour, the addition was complete. After anadditional 30 minutes, the ice bath was removed and the mixture workedup.

Methylene chloride (500 ml) was added. The reaction mixture wasextracted with water (3×1). The organic layer was concentrated on arotary evaporator to yield the 1,4-dihydropyridine as a brown solid (380g, 101%). The solid was recrystallized from hot ethanol to yield thedesired 1,4-dihydropyridine in 80% yield (300 g).

(D) A mixture of 51.6 g (0.3 mol) of 4-fluorophenacylchloride, 33.66 g(0.33 mol) of 2-aminothiazoline and 200 ml of ethanol was heated atreflux for 2 hours. The mixture was cooled to room temperature at whichpoint 300 ml of water was added. After a reflux period of 2 hours, themixture was concentrated to remove about 190 ml of aqueous alcohol. ThepH of the residue was adjusted to about 2 with 10% hydrochloric acid (10ml). The solid product was separated and dried to give 65.4 g (85%) of6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole, m.p. 116-118°.

HPLC conditions: C₁₈ -column, methanol/water/monosodium phosphate,55:45:0.12%.

The procedure of Section D is used to prepare other5-hydrogen-6-substituted-imidazo[2,1-b]thiazole starting materials.

EXAMPLE 2

6-(4-Fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole (10.0 g, 0.0456mol) and 11 ml (0.136 mol) of pyridine (previously stirred overpotassium hydroxide) were dissolved in 150 ml of methylene chloride. Tothis cooled solution (10°) was added 17.75 g (0.13 mol) ofisobutylchloroformate in 20 ml of methylene chloride under a nitrogenatmosphere. During the addition, the reaction pot temperature was notallowed to rise past 10°. After the addition, the reddish-coloredsolution was stirred at ambient temperature for 1 hour then heated underreflux for an additional 15 minutes. Thin-layer chromatography (ethylacetate/hexane/methanol, 15:1:0.1) detected the presence of startingmaterial. An additional 2.13 g (27 mmol) of pyridine, followed by 3.67 g(27 mmol) of isobutyl chloroformate, was added to the reaction vessel.The solution was stirred at room temperature for 1 hour, then, heated toreflux for 15 minutes. Thin layer analysis at this time did not detectstarting material. The reaction mixture was diluted with 200 ml of waterand extracted with methylene chloride (3×100 ml). The organic layer wasdried, then, concentrated to yield 16.0 (85%) of5-(N-isobutyloxycarbonyl-1,4-dihydro-4-pyridyl)-6-[4-fluoro-phenyl)-2,3-dihydroimidazo[2,1-b]thiazole; m.p. 144°-146° (from acetone/hexane).

Calcd. for C₂₁ H₂₂ N₃ O₂ F: C, 63.14; H, 5.55; N, 10.52. Found: C,63.27; H, 5.58; N, 10.49.

EXAMPLE 3

6-(4-Fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole(10.0 g, 0.0456 mol)and 11 ml (0.136 mol) of pyridine were dissolved in 150 ml of methylenechloride. To this cooled solution (10°) was added 20.35 g (0.13 mol) ofphenyl chloroformate in 20 ml of methylene chloride under a nitrogenatmosphere. During the addition, the reaction pot temperature was notallowed to rise past 15°. After the addition, the reddish-coloredsolution was stirred at ambient temperature for 1.5 hours, then heatedunder reflux for an additional 15 minutes. Thin-layer chromatography(ethyl acetate/hexane/methanol, 15:1:0.1) showed the reaction to becomplete. The reaction mixture was diluted with 200 ml of water andextracted with methylene chloride (3×100 ml). The organic layer wasdried, then concentrated to yield 17.0 g (89%) of5-(N-phenyloxycarbonyl-1,4-dihydro-4-pyridyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole;m.p. 164°-166° (from acetone/hexane).

Calcd. for C₂₃ H₁₈ N₃ O₂ FS: C 65.86; H, 4.33; N, 10.02. Found: C,64.84; H, 4.41; N, 9.81.

EXAMPLE 4

6-(4-Fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole (45.0 g, 0.204 mol)and 55 ml (0.68 mol) of pyridine were dissolved in 500 ml of methylenechloride To this cooled (ice-water bath) solution (10°) was added 91.3 g(0.65 mol) of benzoyl chloride in 100 ml of methylene chloride under anitrogen atmosphere. During the addition, the reaction pot temperaturewas not allowed to rise past 10°. After the addition, the desiredproduct precipitated from solution. The addition of the benzoyl chloridesolution was continued. The resulting suspension was stirred at ambienttemperature for 15 minutes, then heated to reflux for 15 minutes.Thin-layer chromatography (ethyl acetate/hexane/methanol, 15:1:0.1)showed the presence of some starting material. An additional 20 ml ofpyridine followed by benzoyl chloride (28 g, 0.2 mol) were added at roomtemperature The suspension was stirred for an additional 0.5 hour.Analysis did not detect starting material at this time The reactionsuspension was filtered. The collected solid was washed with petroleumether. The solid was vacuum dried to yield 66.8 g (81%) of5-(N-phenylcarbonyl-1,4-dihydro-4-pyridyl)6-(4-fluorophenyl)-2,3-dihydroimidazo-[2,1-b]thiazole;m.p. 188°-189°.

Calcd. for C₂₃ H₁₈ N₃ OFS: C, 68.47; H, 4.50; N, 10.41. Found: C, 68.34;H, 4.61; N, 10.28.

EXAMPLE 5

5-(N-Ethyloxycarbonyl-1,4-dihydro-4-pyridyl)-6-phenyl)-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole(2.5 g, 6.7 mmol) was suspended in 3 ml of p-cymene and heated to 175°for 0.45 hours with 0.3 g (9.4 mmol) of sulfur. Thin-layerchromatography (ethyl acetate/methanol, 9:1) demonstrated the reactionto be complete at this time. Ethyl acetate (100 ml) was added to thedark solution which was then extracted with 10% hydrochloric acid (3×50ml). The acidic layer was made basic with aqueous potassium carbonateand extracted with methylene chloride (3×50 ml). The organic layer was,then, dried and concentrated to yield 1.9 g (95%) of crude5-(4-pyridyl)-6-(4-(fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole.Comparison with authentic material by TLC was used to verify theidentity of the product; m.p. 189°.

EXAMPLE 6

5-(N-Phenylcarbonyl-1,4-dihydro-4-pyridyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole(0.5, 1.2 mmol) was dissolved in 2 ml of tert.-butanol containing 0.7 g(6.2 mmol) of potassium tert.-butoxide. Oxygen was bubbled into thesolution which was, then, heated under reflux for 15 minutes. Thesolvent was, then, removed under vacuum and the residue dissolved inmethylene chloride. This organic solution was washed with water (2×50ml), dried and concentrated to yield 0.4 g (87%) of crude5-(4-pyridyl)-6-[4-(fluorophenyl)]-2,3-dihydroimidazo[2,1-b]thiazole.This material was assayed by HPLC to be 79.5% pure. This reaction wasalso carried out in aqueous sodium or potassium hydroxide media.

EXAMPLE 7

Using acetyl bromide and6-(4-chlorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole in the process ofExample 5 gives5-(N-methylcarbonyl-1,4-dihydro-4-pyridyl)-6-(4-chlorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole.

Using benzyl chloroformate and6-phenyl-2,3-dihydroimidazo[2,1-b]thiazole gives5-(N-benzyloxycarbonyl-1,4-dihydro-4-pyridyl)-6-phenyl-2,3-dihydroimidazo[2,1-b]thiazole.

Using methyl chloroformate and6-(2-methylphenyl)-2,3-dihydroimidazo[2,1-b]thiazole gives5-(N-methoxycarbonyl-1,4-dihydro-4-pyridyl)-6-(2-methylphenyl)-2,3-dihydroimidazo[2,1-b]thiazole.

Using phenylacetyl chloride and6-(3-methoxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole gives5-(N-benzylcarbonyl-1,4-dihydro-4-pyridyl]-6-(3-methoxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole.

Using the oxidation conditions of Example 6 for each of thesedihydropyridyl compounds gives the respective5-(4-pyridyl)-6-aryl-2,3-dihydroimidazo[2,1-b]thiazoles.

EXAMPLE 8

4-Acetamidoacetophenone (44 g, 0.25 mole) was suspended in 500 mlmethylene chloride and treated with bromine (44 g, 0.275 mole). Thereaction mixture was stirred overnight, then evaportated in vacuo. Theresidue was suspended in 200 ml of absolute EtOH and treated with2-amino-4,5-dihydrothiazole (60 g, 0.59 mole). The reaction was stirredfor 2 days, then taken up in water and extracted with methylenechloride. The organic phase was washed with water and then brine, andthen dried over sodium sulfate. Flash column chromatography (silica,eluting with methylene chloride / methanol, 98/2) gave6-[4-acetamidopheny])-2,3- dihydroimidazo[2,1-b]thiazole.

The above described acetamide (10.2 g, 0.039 mole) was hydrolyzed inrefluxing 6N HCl (200 ml) for one hour. The mixture was then cooled andneutralized, and extracted with methylene chloride. The organic layerwas washed with brine, dried over sodium sulfate, and evaporated toafford 6.8 g of 6-(4-aminophenyl)-2,3 dihydroimidazo[2,1-b]thiazole.

The above described amine (6.8 g, 0.034 mole) in 150 ml ofdimethylformamide was treated with 1,4-dibromobutane (8.4 g, 0.039 mole)and potassium carbonate (15.5 g, 0.11 mole). The reaction mixture wasstirred at ambient temperature overnight, and the solvent removed invacuo. The residue was flash chromatographed (silica, methylene chloride/ methanol, 97/3) and the crude product recrystallized from methanol toafford 0.88 g of6-(4-(pyrrolidin-1-yl)phenyl2,3-dihydroimidazo[2,1-b]thiazole, mp218-220 (dec). Analyzed for C15 H17 N3 S, Calculated, C: 66.39, H: 6.31,N: 15.48; Found, C: 66.30, H: 6.32, N: 15.27.

The above described pyrrolidine was treated with pyridine and ethylchloroformate as described in Example 1(B) to afford 5-(N-ethoxycarbonyl1,1-dihydro-4-pyridyl)-6-(4-(pyrrolidin-1-yl)phenyl-2,3-dihydroimidazo[2,1-b]thiazole.

EXAMPLE 9

5-bromo-6-(4-fluorophenyl)-2,3-dihydroimidazo[1,2-b]thiazole (1.0 mmol,300 mg, 1 equiv) was weighed into a 50 mL airlessware flask. The flaskwas fitted with a stir bar and was kept under a constant flow of drynitrogen. Tetrahydrofuran (THF, 15 mL, freshly distilled fromsodium/benzophenone) was added and stirring was begun. The reactionmixture was cooled to -78° C. in a dry ice/acetone bath. Butyllithium(1.0 mmol, 2.0M in hexane) was added via syringe in a dropwise manner.The solution was allowed to warm to -30° C. over a 45-minute period, andthen held at that temperature for 10 minutes. The solution was thencooled to -50° C., and magnesium bromide etherate (2 mmol, 516 mg. 2equiv) was added as a solid. The solution was allowed to warm to 0° C.over a 30-minute period and held at that temperature for 15 minutes. Thereaction mixture was then cooled to -20° C., copper iodide (20 mg)added, and the mixture maintained at -20° C. for 10 minutes, after whichdry pyridine (2.0 mmol, 158 mg) was added. After an additional 10minutes, ethyl chloroformate (1.1 mmol, 119 mg) was added in a dropwisemanner. The solution was stirred for 1 hour, during which it was allowedto warm to 20° C. The reaction was then quenched with saturated ammoniumchloride/water (2.0 mL) and poured into water (100 mL). The water wasextracted with methylene chloride (3×50 mL), the organic layer driedover sodium sulfate (anhydrous), and the solvent removed in vacuo toyield a yellow oil which was a mixture of6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole and5-(N-ethoxycarbonyl-1,4-dihydro-4-pyridyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole(260 mg of oil). The latter compound can be purified by silica gelchromatography (solvent =ether/hexane) to provide a 30-40% yield.

EXAMPLE 10

Using acetyl bromide and5-bromo-6-(4-chlorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole in theprocess of Example 9 gives5-(N-methylcarbonyl-1,4-dihydro-4-pyridyl)-6-(4-chlorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole.

Using benzyl chloroformate and5-chloro-6-phenyl-2,3-dihydroimidazo[2,1-b]thiazole gives5-(N-benzyloxycarbonyl-1,4-dihydro-4-pyridyl)-6-phenyl-2,3-dihydroimidazo[2,1-b]thiazole.

Using methyl chloroformate and5-bromo-6-(2-methyl-phenyl)-2,3-dihydroimidazo[2,1-b]thiazole gives5-(N-methoxycarbonyl-1,4-dihydro-4-pyridyl)-6-(2-methylphenyl)-2,3-dihydroimidazo[2,1-b]thiazole.

Using6-bromo-7-(4-fluorophenyl)-2,3-dihydro-4H-imidazo[2,1-b]-)1,3)thiazinein the process of Example 9 gives6-(N-ethoxycarbonyl-1,4-dihydro-4-pyridyl)7-(4-fluorophenyl)-2,3-dihydro-4H-imidazo[2,1-b]-(1,3)thiazine.

What is claimed is:
 1. A compound of the formula ##STR11## in which: Ais a methylene group optionally substituted by methyl, ethyl orgem-dimethyl, or A is a 1,2-ethanediyl group optionally substituted bymethyl, ethyl or gem-dimethyl on either or both carbon atoms of the1,2-ethandiyl group;D is H, methyl, ethyl, or gem-dimethyl; R⁴ is(a)phenyl; (b) monosubstituted phenyl wherein the substituent is halogen,C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, C₁ -C₄ alkyl, CF₃, 2,2,2-triethoxy,prop-2-ene-1-oxy C₁ -C₃ dialkylamino, pyrrolidino or piperidino, orR^(a) C(O)N(CH₂)_(n) CH₃ wherein R^(a) is H, CH₃, CH₂ CH₃ and n is 0 to2; (c) disubstituted phenyl wherein the substituents are independentlyC₁ -C₄ alkyl or C₁ -C₃ alkoxy, or the substituents together form amethylene-dioxy group; or (d) 3,4,5-trimethoxyphenyl; and X, is Cl, Br,or I.
 2. The compound of claim 1 in which R⁴ is phenyl or phenylmonosubstituted with halogen, C₁ -C₂ alkyl, CF₃, pyrrocidino orpiperidino.
 3. The compound of claim 2 in which X' is Br.
 4. Thecompound of claim 1 in which A is an unsubstituted methylene and D ishydrogen.
 5. The compound of claim 1 in which A is an unsubstituted1,2ethanediyl and D is hydrogen.